The therapeutic utility of inhibiting/modulating progesterone receptor (PR) transcriptional activity in uterine fibroids has been well validated both in preclinical models of this disease and in several definitive clinical studies. Indeed, both antiprogestins and Selective Progesterone Receptor Modulators (SPRMs) have been shown to reduce fibroid volume, control bleeding and reduce pelvic pressure. Unfortunately, whereas acute responses in fibroids to both classes of PR modulators have been favorable in terms of efficacy and general side effect profile, they also induce distinct endometrial changes that are characterized by asynchrony between endometrial glands and stroma with occasional cystic dilatation of these same glands. Although the clinical consequences of these unexpected endometrial responses are unclear, they have emerged as an impediment to the use of antiprogestins and SPRMs for all but short-term use as treatments for fibroids. Although it is unlikely that the long-term studies required to justify chronic administration of the currently available antiprogestins/SPRMs will be performed, the fact remains that PR is the best-validated drug target for extended treatment of this disease. Given the importance of this clinical problem and the unmet need for medical interventions that either mitigate the symptomatic presentation of the disease or improve surgical outcomes, it is our opinion that a mechanism-based approach toward PR modulator discovery may yield drugs with improved pharmaceutical profiles. From our studies of the mechanism of action of nuclear receptor (NR) pharmacology over the past few years, we have learned that the relative agonist/antagonist activity of specific receptor modulators is determined by (a) the impact of ligands on the structure of the receptor, (b) the differential interaction of cofactors1 with differently conformed NR-ligand complexes, and (c) the relative expression level and activity of relevant cofactors in target cells. We have exploited this concept to develop several new classes of functionally distinct androgen receptor (AR) modulators for the treatment of cancer and other androgenopathies and a new antiestrogen that is currently being evaluated in patients with metastatic breast cancer. Similarly, we propose to evaluate the role(s) of specific coactivators and corepressors in mediating the biological responses to progestins and antiprogestins in cellular models of uterine fibroids and relate these findings to the biology of fibroids. These studies will provide basic insights into the molecular mechanisms of action of progestins and antiprogestins that are likely to translate to other systems. However, we also anticipate that this investigation will lead to development and validation of new approaches with which to identify novel antiprogestins/SPRMs that effectively treat fibroids but which do not manifest abnormal pathological responses in the endometrium.